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Fluorine-substituted diphenylethane compound and preparation method and application thereof

A technology of diphenylethane and compounds, applied in the field of drug synthesis, can solve the problems of harsh reaction conditions, tumor cell apoptosis, and many by-products, and achieve simple and easy preparation conditions, strong in vitro anti-tumor activity, and few by-products Effect

Active Publication Date: 2019-09-17
SHANGHAI INST OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, it has been reported in the literature that the anti-tumor effect of erianin may also be related to the induction of tumor cell apoptosis by acting on telomerase.
[0003] There have been many reports on stilbene fluorine-substituted modifiers, most of which are monofluoro-substituted and trifluoromethyl-substituted, but there are no reports on derivatives substituted by bridging fluorine, and the synthesis theory of derivatives substituted by bridging fluorine is more complex. Large, the current synthesis steps of bridge fluorine-substituted derivatives are relatively complicated, the requirements are harsh, and there are many by-products. The current synthesis method is not suitable for large-scale production, and the synthesis conditions need to be further optimized.
However, the above technical scheme requires anhydrous and oxygen-free conditions during the experimental operation, the reaction conditions are harsh, there is no stereoselectivity, and the yield is low

Method used

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  • Fluorine-substituted diphenylethane compound and preparation method and application thereof
  • Fluorine-substituted diphenylethane compound and preparation method and application thereof
  • Fluorine-substituted diphenylethane compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Synthesis of (E)-2-(4-methoxyphenyl)-3-(3,4,5-trimethoxyphenyl)acrylic acid (3a), see figure 1 :

[0043]Dissolve 3,4,5-trimethoxybenzaldehyde (7.9g, 40mmol) and p-methoxyphenylacetic acid (6.7g, 40mmol) in 150mL of acetic anhydride, then add triethylamine (8.1g, 80mmol) , The mixture was heated at 110° C. for 6 h. After cooling, it was acidified with concentrated hydrochloric acid, poured into ice water, and stirred for 4 hours to obtain a light yellow solid, which was filtered, dissolved in 10% NaOH aqueous solution, washed with ethyl acetate to decolorize, separated the organic layer, and kept the aqueous phase. Hydrochloric acid was added to the aqueous phase until pH = 3-4. The precipitated solid was filtered and recrystallized from ethyl acetate to obtain 3a, 11.0 g, yield 80.2%, white solid, mp: 188.6-189.3°C.

[0044] 1 H NMR (500MHz, CDCl 3 ): δ7.82(s,1H),7.20(d,J=10.0Hz,2H),6.96(d,J=5.0Hz,2H),6.37(s,2H),3.81(s,6H),3.58 (s,6H);

[0045] 13 C NMR (125MHz...

Embodiment 2

[0078] Preparation of 1-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethan-1-ol (7a), see figure 1 :

[0079] 5a (1.6 g, 5 mmol) was dissolved in 30 mL of absolute ethanol, and NaBH was added in portions at 0 °C 4 (0.3g, 7.5mmol), stirred for half an hour, returned to room temperature and reacted overnight. Quenched with water, extracted with ethyl acetate, combined organic phases, dried over anhydrous sodium sulfate, filtered, and spin-dried, the residue was purified by silica gel chromatography to obtain 7a (1.0 g, yield 65.0%), which was directly used in the next reaction.

[0080] Preparation of 5-(2-fluoro-2-(4-methoxyphenyl)ethyl)-1,2,3-trimethoxybenzene (8a):

[0081] It is one of the fluorine-substituted diphenylethane compounds in the present invention.

[0082] Dissolve 7a in dichloromethane, add DAST (0.8g, 4.7mmol) dropwise at 0°C and stir for half an hour, return to room temperature, stir for 18h, TLC monitors that the reaction is complete, drop ice water to que...

Embodiment 3

[0084] For the preparation of 1-(3-(benzyloxy)-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethan-1-ol (7b), see figure 1 :

[0085] 5b (1.6g, 5mmol) was dissolved in 30mL of absolute ethanol, NaBH4 (0.3g, 7.5mmol) was added in batches at 0°C, stirred for half an hour, returned to room temperature and reacted overnight. Quenched with water, extracted with ethyl acetate, combined organic phases, dried over anhydrous sodium sulfate, filtered, and spin-dried, the residue was purified by silica gel chromatography to obtain 7b (1.3 g, yield 64.5%), which was directly used in the next reaction.

[0086] Preparation of 5-(1-fluoro-1-(3-(benzyloxy)-4-methoxyphenyl)ethyl)-1,2,3-trimethoxybenzene (8c), which is the subject of the present invention One of the fluorine-substituted diphenylethane compounds. see figure 1 .

[0087] Dissolve 7b in dichloromethane, add DAST (0.8g, 4.7mmol) dropwise at 0°C and stir for half an hour, return to room temperature, stir for 18h, TLC monitors that...

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Abstract

The invention relates to a fluorine substituted diphenylethane compound, which is characterized in that the structure is shown as a general formula (I): wherein R1 is methyl or ethyl; R2 is hydrogen or fluorine; and R is hydrogen, hydroxyl, benzyloxy, phosphate and phosphate salt. Compared with the prior art, fluorine substitution modification is performed on the bridge bond of diphenylethane, and the obtained fluorine substituted diphenylethane compound has stronger in vitro anti-tumor activity, the introduction of fluorine atoms changes the physical, chemical and biological properties of the compound, and the fluorine substituted diphenylethane compound has obvious inhibition effect on tumor cells. The preparation conditions are simple and easy to operate, and by-products are less.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a fluorine-substituted diphenylethane compound, a preparation method and application thereof. Background technique [0002] Erianin, whose chemical name is 3,4,5-trimethoxy-3'-hydroxy-4'-methoxydiphenylethane (code: MLS), is a natural Diphenylethane active ingredients have anti-tumor effect. Erianin has the same structural features as the stilbene natural product Combretastatin A-4 (code name CA4, also known as windmill) in structure, and has a common AB ring structure. Erianin is equivalent to the vinyl bridge being hydrogenated the CA4. Like CA4, Erianin is also a tubulin inhibitor and has a strong tumor vessel-targeted destruction effect, acting on the colchicine binding site. In addition, it has been reported in the literature that the anti-tumor effect of erianin may also be related to the induction of tumor cell apoptosis by acting on telomerase. [0003] There h...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C41/22C07C43/225C07F9/12A61P35/00A61P35/02A61P29/00A61P19/02A61P3/10A61P27/02A61P17/06A61P17/10A61P27/06A61P31/04A61P31/10A61P1/04A61P33/02A61P31/18A61P31/22
CPCA61P1/04A61P3/10A61P17/06A61P17/10A61P19/02A61P27/02A61P27/06A61P29/00A61P31/04A61P31/10A61P31/18A61P31/22A61P33/02A61P35/00A61P35/02C07C43/225C07F9/12
Inventor 黄金文李英姿黄磊磊李玉洁吴范宏舒海英
Owner SHANGHAI INST OF TECH
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